Piperazinomethyl 2,3 dihydro 5 phenyl 1-benzothiepins



United States Patent 3,520,891 PIPERAZINOMETHYL 2,3 DIHYDRO PHENYLl-BENZOTHIEPINS Richard J. Mohrbacher, Fort Washington, Pa., assignor toMcNeil Laboratories, Incorporated, a corporation of Pennsylvania NoDrawing. Application Aug. 16, 1968, Ser. No. 753,067, which is adivision of application Ser. No. 636,570, Apr. 28, 1967, which in turnis a continuation-in-part of application Ser. No. 462,411, June 8, 1965.Divided and this application May 22, 1969, Ser. No. 842,065

Int. Cl. C07d 51/70 US. Cl. 260-268 5 Claims ABSTRACT OF THE DISCLOSUREThe compounds are of the class of 2,3-dihydrobenzothiepins, useful fortheir pharmacological properties as hypotensive agents.

This application is a division of my co-pending application Ser. No.753,067, filed Aug. 16, 1968, which in turn is a division of applicationSer. No. 636,570, filed Apr. 28, 1967 (issued on May 13, 1969, as US.Pat. No. 3,444,176), which in turn is a continuation-in-part ofapplication Ser. No. 462,411, filed June 8, 1965, now abandoned.

This invention relates to certain novel dihydrobenzothiepins. Moreparticularly, it concerns dihydrobenzothiepins having the formula RRiwherein R is a member of the group consisting of 2-pyridyl, 3-pyridyland 4-pyridyl; R is a member of the group consisting of hydrogen anddiloweralkylaminomethyl; and the non-toxic acid addition salts and thetherapeutically active loweralkyl quaternary ammonium derivativesthereof. R may be phenyl, in which event when R is hydrogen, no acidaddition salts or loweralkyl quaternary ammonium derivatives arepossible. R may be a member selected from the group consisting ofpiperidinomethyl, pyrrolidinomethyl and morpholinomethyl; likewise, Rmay be a member selected from the group consisting of piperazinomethyl,N-loweralkylpiperazinomethyl and N-aryl-piperazinomethyl.

As used herein loweralkyl may be straight or branch chained and havefrom 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tertiary butyl and the like.

The therapeutically active non-toxic acid addition salts of the basicnitrogen containing compounds are prepared by treatment with anappropriate acid such as an inorganic acid, e.g., hydrochloric,hydrobromic, hydriodic, sulfuric, nitric or phosphoric; an organic acidsuch as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic,maleic, malic, fumaric, tartaric, citric, benzoic, mandelic cinnamic,methane sulfonic, benzene sulfonic, salicylic, 2- phenoxybenzoic.Conversely, the salt form may be converted in the usual manner into thefree base.

The novel basic nitrogen containing compounds may be converted into thecorresponding quaternary ammonium compounds by reaction of the tertiarybases with alkylating agents, i.e., alkyl or aralkyl halides or estersformed by reacting alkanols with an oxygen-containing acid such asmethyl iodide, ethyl bromide, propyl chloride; lower alkenylha1idesallyl bromide; dilower a1kylsulfates-dimethylsulfate,diethylsulfate; lower alkylarylsufonates- 3,520,891 Patented July 21,1970 methyl p-toluenesulfonate or aralkyl halidesbenzyl chloride. Thequaternizing reaction may be performed in the presence or absence of asolvent, at room temperature or under cooling, at atmospheric pressureor in a closed vessel under pressure. Suitable solvents for this purposeare ethers such as diethylether and tetrahydrofuran, hydrocarbons suchas benzene and heptane, ketones such as acetone, and butanone,loweralkanols such as ethanol, propanol or butanol; or organic acidamides such as formamide or dimethylformamide. When lower alkylhalogenides are used as quaternizing agents, diethyl ether and benzeneare the preferred solvents.

The compounds of this invention have been found to possess valuablepharmacological properties. These compounds are useful as hypotensiveagents as demonstrated by their ability to lower blood pressure in dogsfollowing intraveneous administration. For example, with those compoundsin which R is phenyl or 2-pyridyl and R is hydrogen ordimethylaminomethyl, intraveneous administration of 10 mg./kg. of bodyweight to an anesthetized dog causes a blood pressure lowering of 48 mm.of Hg. The corresponding acid addition salts have the same utility asthe basic nitrogen containing compounds.

The compounds of this invention are prepared by dehydrating thecorresponding 5-substituted and 4-substituted 5substituted-2,3,4,5-tetrahydro-1-benzothiepin 5-ols, wherein the 5 and 4substituents are the respective members defined hereinabove. Thedehydration is undertaken by mixing the precursor compounds with asuitable catalyst such as sulfuric acid, potassium acid sulfate orhydrochloric acid, heating the mixture at reflux, cooling, rendering thereaction mixture basic and extracting the dehydrated compounds withmethylene chloride.

The 2,3,4,5-tetrahydro-l-benzothiepin-S-ol precursors wherein R isphenyl or pyridyl and R is hydrogen, loweralkylaminomethyl,diloweralkylaminomethyl, or cyclic aminomethyl, such aspiperidinomethyl, pyrrolidinomethyl, morpholinomethyl, piperazinomethyl,N-loweralkylpiperazinomethyl or N-aryl-piperazinomethyl, are prepared byslowly adding a solution of a 4-substituted-3,4-dihydro-1-benzothiepin-5(2H)-one (wherein the 4-substituent is an Rmember as defined above) in a suitable solvent such as benzene to asolution of pyridyl lithium or phenyl lithium in a suitable inertorganic solvent such as those mentioned hereinabove which has beencooled.

The following examples are intended to illustrate, but not to limit, thescope of the present invention.

EXAMPLE I A solution of 2-pyridyl lithium is prepared by the addition of20 g. (0.126 mole) of 2-bromopyridine to a stirred solution of butyllithium (0.12 mole in ml. of hexane) in 400 ml. of anhydrous ether at-40 C. After 15 minutes, 17.8 g. (0.1 mole) of3,4-dihydro-1-benzothiepin-5(2H)-one in 100 ml. of benzene is added overa period of 5 minutes. During the next hour, the temperature risesgradually from 40 C. to room temperature. The slurry is poured intodilute, iced hydrochloric acid. Crystalline hydrochloride saltprecipitates and is removed by filtration. Conversion of the acid saltto the free base yields 10.4 g. of crystalline free base. Basificationof the original acidic filtrate followed by benzene extraction yields,after concentration of the organic layer, an additional bath of basecrystals. Three recrystallizations from cyclohexane-hexane producescrystals; M.P., 7980.5 C. The product is 2,3,4,5 tetrahydro-S-(Z-pyridyl) -1-benzothiepin-5-ol.

EXAMPLE II A mixture of 17.8 g. (0.1 mole) of 3,4-dihydro-1-benzothiepin 5 (2H) one, 10.6 g. (0.13 mole) of dimethylaminehydrochloride, 3.96 g. (0.044 mole) of paraformaldehyde and 0.2 ml. ofconcentrated hydrochloric acid in 20 ml. of 95 percent ethanol isrefluxed with stirring for 3 hours. After slight cooling 80 ml. ofacetone is added. Cooling in the refrigerator yields White crystals. Tworecrystallizations from 95 percent ethanolacetone produces whitecrystals of 4 dimethylaminomethyl-3,4-dihydro-l-benzothiepin 5(2H) onehydrochloride; M.P., 182-4 C.

EXAMPLE III A solution of 58.8 g. (0.25 mole) of4-dimethylaminomethyl-3,4-dihydro-l-benzothiepin-S(2H)-one in 500 ml. ofbenzene is added over a period of minutes to a solution of 0.55 mole ofphenyl lithium (prepared from bromobenzene and lithium) in 840 ml. ofether. The reaction mixture is stirred at reflux for 22 hours. Aftercooling, the mixture is decomposed with 300 ml. of water. The organiclayer is separated and the aqueous phase is extracted with ether. Thecombined ethereal solution is washed with Water, then with saturatedbrine, and dried over magnesium sulfate. After removal of the dryingagent, benzene is added, causing precipitation of White crystals. Onerecrystallization from ethyl acetate petroleum ether (3060 C.) yieldswhite crystals of 4-dimethylaminomethyl 2,3,4,5 tetrahydro 5 phenyl 1-benzothiepin-S-ol; M.P., 135-140 C.

EXAMPLE IV A solution of 2-pyridyl lithium is prepared by the additionof g. (0.126 mole) of 2-bromopyridine to a stirred solution of butyllithium (0.12 mole in 100 ml. of hexane) in 400 ml. of anhydrous etherat 40 C. After 15 minutes 23.5 g. (0.1 mole) of4-dimethylaminomethyl-3,4-dihydro-1-benzothiepin-5(2H)-one in 100 ml. ofbenzene is added over a period of 10 minutes. The temperature isgradually raised from 40 C. to reflux and maintained there for 22 hours.After cooling, the mixture is decomposed with 150 ml. of water. Theorganic layer is separated and the aqueous phase is extracted withether. The combined ethereal solution is washed with Water, thensaturated brine, and dried over magnesium sulfate. After removal of thedrying agent, the solution is evaporated to dryness to obtain4-dimethylaminomethyl-2,3,4,5-tetrahydro-5-(2-pyridyl) 1benzothiepin-S-ol.

EXAMPLE V A solution of 17.8 g. (0.1 mole) of 3,4-dihydro-1-benzothiepin-5(2H)-one in 100 ml. of benzene is added over a period of10 minutes to a solution of 0.2 mole of phenyl lithium (prepared frombromobenzene and lithium) in 500 ml. of arhydrous ether With cooling.During the next hour the temperature is allowed to rise gradually toroom temperature. The mixture is decomposed with 150 ml. of water. Theorganic layer is sep arated and the aqueous phase is extracted Withether. The combined ethereal solution is washed with water, then withsaturated brine, and dried over magnesium sulfate. After removal of thedrying agent, and concentration of the organic phase, addition of hexaneresults in precipitation of2,3,4,S-tetrahydro-S-phenyl-l-benzothiepin-S-ol.

EXAMPLE VI Using the procedure of Example I and replacing 2-bromopyridine with equivalent amounts of 3 bromopyridine and4-bromopyridine, the products obtained are 2,3,4,5-tetrahydro-5-3-pyridyl) -1-benzothiepin-5-ol; 2,3,4,5-tetrahydro-5- (4-pyridyl)-1-benzothiepin-5-ol.

EXAMPLE VII Using the procedure of Example II and replacingdimethylamine hydrochloride with equivalent amounts of the hydrochloridesalt of diethylamine, dipropylamine, diisobutylamine, and dibutylamine,the products obtained are 4-diethylaminomethyl-3,4-dihydrol-benzothiepin- 5 (2H) -one;4-dipropylaminomethyl-3,4-dihydrol-benzothiepin- 5 (2H -one;4-diisobutylaminomethyl-3 ,4-dihydrol-benzothiepin- 5 2H) -one;4-dibutylaminomethyl-3,4-dihydro-1-benzothiepin- 5 (2H -one.

EXAMPLE VIII Using the procedure of Example II and replacingdimethylamine hydrochloride With equivalent amounts of the hydrochloridesalt of piperidine, pyrrolidine, morpholine, piperazine,N-methyl-piperazine, N-ethyl-piperazine, N-butyl-piperazine, andN-phenyl-piperazine, the products obtained are4-piperidinomethyl-3,4-dihydro-1-benzothiepin- 5 2H -one;

4-pyrrolidinomethyl-3 ,4-dihydrol-b enzothiepin- 5 2H -one4-morpholinomethyl-3 ,4-dihydrol-b enzothiepin- 5 2H) -one;

4-piperazinomethyl-3 ,4-dihydrol-benzothiepin- 5 2H) -one;

4-N-methyl-piperazinomethyl-3,4-dihydro-1- benzothiepin-S 2H -one;

4-N-ethyl-piperazinomethyl-3 ,4-dihydro-1- benzothiepin-S 2H) -one;

4-N-butyl-piperazinomethyl-3 ,4-dihydro- 1- benzothiepin-S (2H -one;

4-N-phenyl-piperazinomethyl-3 ,4-dihydro-1- benzothiepin-S (2H) -one.

EXAMPLE IX Using the procedure of Example III and replacing 4- dimethylaminomethyl 3,4, dihydro 1 benzothiepin-S (2H)-one with equivalentamounts of each of the prodnets of Example VII, the products obtainedare 4-diethylaminomethyl-2,3,4,5-tetrahydro-5-phenyl-1-benzothiepin-S-ol 4-dipropylaminomethyl-2,3,4,5-tetrahydro-4-phenyl-1-benzothiepin-5-ol;

4-diisobutylaminomethyl-Z,3,4,S-tetrahydro-S-phenyll benzothiepin-S-ol;

4-dibutylaminomethy1-2,3,4,S-tetrahydro-S-phenyl-1- benzothiepin-S-ol.

EXAMPLE X Using the procedure of Example III and replacing 4-vdimethylaminomethyl 3,4 dihydro l benzothiepin-S (2H)-one withequivalent amounts of each of the products of Example VIII, the productsobtained are EXAMPLE XI Using the procedure of Example IV and replacing4-dimethylaminomethyl 3,4 dihydro 1 benzothiepin 5 (2H)-one withequivalent amounts of each of the products of Example VII, the productsobtained are:

4-diethylaminoethyl-2,3,4,5-tetrahydro-5-(Z-pyridyl)-lbenzothiepin-S-ol;

4-dipropylaminomethyl-2,3,4,5-tetrahydro-5- (2-pyridyl)l-benzothiepin-S-ol;

4-diisobutylaminomethyl-2,3,4,S-tetrahydrO-S- (2-pyridyl)- 64-dipropylaminomethyl-2,3-dihydro-5 -phenyl-1-benzothiepin;4-diisobutylaminomethyl-Z,3-dihydro-5-phenyll-benzothiepin;4-dibutylaminomethyl-2,3,-dihydro-5-phenyl-l-benzol-benzothiepin-S-ol; 5P 4-dibutylaminomethyl-2,3,4,5-tetrahydro-5-( 2-pyridyl) EXAMPLE XVI 1benzothlepm 5 Using the procedure of Example XIII and replacing EXAMPLEXII 1O 2,3,4,5 tetrahydro 5 (2 pyridyl) 1 benzothiepin-S-ol Using theprocedure of Example IV and replacing 4- wlth equwalents amounts each ofthe fol'lowmg dimethylaminomethyl 3,4 dihydro 1 benzothiepin-S- y -py yp (2H)-one with equivalent amounts of each of the prod- Y -PY Y P l;ucts of Example VIII, the products obtained are4'dimethylamiflomethyl-2,3,4,5-ttfahYdf0'5 -Py Y 15 l-benzothiepin-S-ol;-p p y y -p D- 4-diethylaminomethyl-2,3,4,5-tetrahydro-5(2-pyridyl)-1-benzothiepin-S-ol; lbenzothiepin-s-ol; -PY Y Y4-dipropylaminomethyl-2,3,4,5-tetrahydro-S (2-pyridyl) -1-belllothiepins-ol; benzothiepin-S-ol; 4-II10f P f Y y -py4-diisobutylaminomethyl-Z,3,4,5-tetrahydro-5 (2-pyridyl)b6I1Z0thieP1I1-5-01; l-benzothiepin-S-ol; 'P P P Y Y -py y4-dibutylaminomethyl-2,3,4,5-tetrahydro-5 (2-pyridyl) -1- fp h 1 4 5 h d5 2 benzothiepin-S-ol; 4 ggggifigggl i tetra y m the following productsare obtained: 4-N-ethyl-piperazinomethyl-2,3,4,5-tetrahydro-5- (2-2,3-dihydro-5 (3-pyridyl) -1-benzothiepin; pyridyl)-1-benzothiepin-5-ol; 2,3-dihydr0-5 (4-pyridyl) -1-benzothiepin;4-N-butyl-piperazinomethyl-Z,3 ,4,5-tetrahydro-5- (2-4-dimethylaminomethyl-2,3-dihydro-5 (2-pyridyl) -1-pyridyl)-1-benzothiepin-5-ol; benzothiepin;4-N-phenyI-piperaZinQmethyl-Z,3,4,5-tetrahydro-5-(2-4-diethylaminomethyl-2,3-dihydro-52-pyridyl)-1-benzopyridyl)-1-benzothiepin-5-0l. thiepin;

4-dipropylanlinomethyl-2,3-dihydro-5 (2-pyridyl) -1- EXAMPLE XIIIbenzothienin: A 19.3 g. 0.75 mole) sample of 2,3,4,5-tetrahydro-5- y p-p y (2-pyridyl)-l-benzothiepin-5-ol is mixed with 300 ml. of b p 2 Msulfuric acid and heated at reflux temperature for 19 q y y y -py U-hours. After cooling, the material is carefully made basic thleplnandthen is extracted with methylene chloride. The meth- EXAMPLE XVII ylenechloride is rem9ved i vacuo to give black Using the procedure of ExampleXIII and replacing $2522;telesales;lasllzlirfizgziiiiz 1 give whitecrystals of 2,3-dihydro-5-(2-pyridyl)-1-benzoeqmvalent amounts of eachthe followmg thiepin; M.P. 77-78.5 C.4-piperidinomethyl-2,3,4,S-tetrahydro-S-phenyl-l-benzothiepin-S-ol;EXAMPLE XIV 4-pyrrolidinomethyl-2,3,4,S-tetrahydro-S-phenyl-l-benzo- Asolution of 24 g. (0.0767 mole) of 4-dimethylaminop I methyl 2,3,4,5tetrahydro-S-phenyl-l-benzothiepin-S-ol Q PP y -L ,5-tetrahydro-5-plenyl-l-benzoin 500 ml. of 2 M sulfuric acid is refluxed for 19 hours. que- An oil separates and crystallizes during the heating period. 'P B YY -P y After cooling the solid is collected and recrystallized from Pacetone-methanol-ether to give a white, crystalline sulfate Y -P P Y ysalt. One recrystallization from 2-propanol-ether yields P y 'P F Pwhite crystalline 4-dimethylamino-2,3-dihydrO-S-phenyl-1- Y -P P FIHIIYI-Z,3,4,S-tetrahydro-S-phenylbenzothiepin sulfate; MiP. 213 c.1-benZ0th1ePm-5-01;

4-N-butyl-piperazinomethyl-2,3,4,5-tetrahydro-5-phenyl- EXAMPLE XVl-benzothiepin-S-ol; Using the procedure of Example XIII and replacin$31 353?fifigf 2,3,4; -tetrahydro-S-(Z-pyridyl)-1-benzothiepin-5-ol withP equivalent amounts of each of the following th f fl i products are b id; 3 5-tetTahYdFO-5 -P Y l-benlothiepin-54-piperidinomethyl-2,3-dihydro-5 -phenyl-1-benzothiepin y y y -p y4-pyrrolidinomethyl-2,3-dihydro-5-phenyl-l-benzothiepin;belllothiepiIl-5-ol;4-morpholinomethyl-2,3-dihydro-5-phenyl-l-benzothiepin; p p y y -P Y4-piperazinomethyl-2,3-dihydro-5-phenyl-l-benzothiepin;

benzothiepin-S-ol; 4-N-methyl-piperazinomethyl-Z,3-dihydro-5-pl1enyl-1-4-diisobutylaminomethyl-Z,3,4,S-tetrahydro-S-phenyl-1- benzothiepin;

benzothiepin-S-ol; 4-N-ethyl-piperazinomethyl-Z,3-dihydro-5-phenyl-1-4-dibutylaminomethyl-2,3,4,S-tetrahydro-S-phenyl-lbenzothiepin;

benzothiepin-S-ol; 4-N-butyl-piperazinomethyl-2,3-dihydro-5-phenyl-1-benzothiepin; the followlng Products 6 Obtained:4-N-phenyl-piperazinomethyl-Z,3-dihydro-5-phenyl-1- benzothiepin.2,3-dlhydro-5-phenyl-l-benzothlepln, 4-diethylaminomethyl-2,3-dihydro-5-phenyl-l-benzo- EXAMPLE XVIII thiepin;Using the procedure of Example XIII and replacing 7 2,3,4,5 tetrahydro 5(2 pyridyl) 1 benzothiepin-S-ol with equivalent amounts of each of thefollowing 4-piperidinomethyl-2,3,4,5-tetrahydro-5 (2-pyridy1) -1-benzothiepin-S-ol; 4-pyrrolidinomethyl-2,3 ,4,5-tetrahydr0-5(2-pyridy1)-1- henzothiepin-S-ol;4-rnorpholinomethy1-2,3,4,5-tetrahydro-5 (Z-pyridyl) -1-benzothiepin-S-ol; 4-piperazinomethyl-2,3,4,5-tetrahydro-5(2-pyridy1)-1-benzothiepin-S-ol; 4-N-methyl-piperazinomethyl-2,3,4,5-tetrahydro-5 2-pyridyl) -1-benzothiepin-5-ol;4-N-ethyl-piperazinomethyl-2,3,4,5-tetrahyd1'0-5 (2-pyridyl)-1-benzothiepin-5-o1; 4-N-buty1-piperazinomethyl-2,3,4,5-tetrahydro-5 (2- pyridyl)-1-benzothiepi11-5-ol;4-N-phenyl-piperazinornethyl-Z,3,4,S-tetrahydro-S (2-pyridyl)-1-benz0thiepin-5-ol;

the following products are obtained:

4-piperidinomethyl-2, 3 -dihydro-5 (2-pyridyl)-1-benzothiepin;

4-pyrrolidinomethyl-2,3-dihydro-5 (2-pyridyl) -1-benzothiepin;

4-morpholinomethyl-2,3-dihydro-5 (2-pyridyl)-1-benzothiepin;

4-piperazinomethyl-2,3-dihydro-5 (Z-pyridyD-l-benzothiepin;

4-N-methyl-piperazinomethyl-Z,3-dihydro-5 (2-pyridy1) 1-benzothiepin;

4-N-ethyl-piperazinomethyl-Z,3-dihydro-5 (2-pyridyl) l-benzothiepin;

4-N-butyl-piperazinomethyl-Z,3-dihydro-5 (2-pyridyl) l-benzothiepin;

4-N-phenyl-piperazinomethyl-2,3-dihydro-5 (Z-pyridyl) 7-benzothiepin. 1

I claim: 1. A member selected from the group consisting of2,3-dihydro-1-benzothiepins having the formula References Cited UNITEDSTATES PATENTS 3,287,370 11/1966 Mohnbacher et a1. 260327 3,332,9567/1967 Crenshaw 260268 X DONALD G. DAVIS, Primary Examiner 22733 UNITEDSTATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,5 9 DatedJuly 97 Inventor-(3) Richard J- Mohr'bacher It is certified that errorappears in the above-identified patent and that said Letters Patent arehereby corrected as shown below:

Column line +1, the phrase "tetrahydrol-phenyl" should readtetrahydro-S-phenyl SliiiiED Ausillfl mva m (SEAL) Auesu Edward M- W 1Amazing 0mm amma, 38- W a. Patents

